Project Summary/Abstract There is a fundamental gap in understanding how environmental exposures affect the development and clinical expression of amyotrophic lateral sclerosis (ALS). Continued existence of this gap represents an important problem, because until it is filled, understanding how specific environmental toxins affect the pathophysiology of ALS (1) hampers the ability to delineate ALS mechanisms and thereby limit treatment opportunities and (2) prevents the removal of modifiable risk factors from the environment. The long-term goals are to determine the influence of environmental toxins on the genetic susceptibility and pathogenesis of ALS, contextualize our data to support the National ALS registry, and promote therapeutic and biomarker discovery. The overall objective of this application is to identify persistent organic pollutants that associate with ALS disease expression. The central hypothesis is that persistent organic pollutants alter ALS incidence and disease factors such as surviv- al. The rationale for the proposed research is that discovering and delineating the impact of environmental tox- ins on ALS can identify a modifiable disease risk and also inform our understanding of the disease?s patho- physiology. Guided by strong preliminary data, this hypothesis will be tested by pursing two specific aims: 1) Determine how exposure to persistent organic pollutants modifies ALS disease expression in patients followed at the University of Michigan ALS Clinic; and 2) Expand the assessments of ALS and environmental exposures statewide to determine if geospatial clusters of ALS occur in Michigan and characterize their relationship to known sites of environmental pollution. Under the first aim the impact of environmental exposures--derived via a detailed questionnaire combined with measured persistent organic pollutant levels in blood--on region of on- set, survival, and disease progression will be determined. Under the second aim, a case-control study, com- prised of all newly diagnosed individuals with ALS and healthy controls, will determine the presence of geospa- tial clusters of ALS in State of Michigan. The proposed research is innovative, in the applicant?s opinion, be- cause it represents a substantive departure from the status quo by explicitly identifying how persistent organic pollutants alter ALS disease expression and how geospatial factors, such as persistent environmental pollu- tants, alter ALS susceptibility which will pave the way for improved pathophysiologic studies on ALS. New re- search horizons are expected to become attainable as a result. The proposed research is significant, because it will identify factors that can mitigate the risk of developing ALS and furthermore guide future studies on new pathophysiologic mechanisms of ALS. Ultimately, such knowledge has the potential to improve the pathophys- iologic understanding of ALS and other neurodegenerative diseases.